Suzuki-Miyaura coupling based enantioselective synthesis of (+)-epi- Clausenamide and the enantiomer of its 3-deoxy analogue

Article abstract of DOI:10.1055/s-0031-1290804

The first enantioselective synthesis of two biologically interesting close analogues of clausenamide, namely (+)-epi-clausenamide and (-)-3-deoxy-epi- clausenamide, was reported. Key steps of the synthesis included construction of the chiral pyrrolinone intermediates from d- and l-serine derivatives, introduction of the C4-phenyl by Suzuki-Miyaura coupling and establishment of the C6 configuration by a threo-selective Grignard reaction. Optimization of the key Suzuki-Miyaura coupling reaction was described in detail. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290804

LETTER
▌1217
lSetuterzuki–Miyaura Coupling Based Enantioselective Synthesis of (+)-epi-
Clausenamide and the Enantiomer of Its 3-Deoxy Analogue
Enantioselective Synthesis of (+)-epi-Clausenamide
Lu Zhang, Yumei Zhou, Xiaoming Yu*
State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Beijing Key Laboratory of Active Substance Discovery and
Drugability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050,
P. R. of China
Fax +86(10)63017757; E-mail: mingxyu@imm.ac.cn
Received: 13.01.2012; Accepted after revision: 16.03.2012
ble in the synthesis of 2 and 3 albeit their high resem-
Abstract: The first enantioselective synthesis of two biologically
blance to 1, because the reduction of 5 is highly erythro-
interesting close analogues of clausenamide, namely (+)-epi-
selective and compound 1 is usually the only product re-
gardless the reducing agent. Therefore, different synthetic
clausenamide and (–)-3-deoxy-epi-clausenamide, was reported.
Key steps of the synthesis included construction of the chiral pyrro-
linone intermediates from D- and L-serine derivatives, introduction routes are to be sought. We recently finished an optical
resolution based synthesis of (+)-2,8 and herein report a
Suzuki–Miyaura coupling based enantioselective synthe-
of the C4-phenyl by Suzuki–Miyaura coupling and establishment of
the C6 configuration by a threo-selective Grignard reaction. Opti-
mization of the key Suzuki–Miyaura coupling reaction was de-
sis of (+)-2 and (–)-3 from D- and L-serine, respectively.
scribed in detail.
Key words: (+)-epi-clausenamide, (–)-3-deoxy-epi-clausenamide,
nootropics, osteoporosis, Suzuki–Miyaura coupling
H
H
OH
H
OH
3
4
5
H
H
H
2
O
O
O
Clausenamide [(±)-1, Figure 1] is a densely substituted
pyrrolinone natural product found in the aqueous extract
of Chinese herb medicine Clausen alassium (lour) skeels.1
The compound contains four chiral centers, but was iso-
lated as a racemate. Instead of the originally anticipated
hepatoprotective property, the levo-enantiomer of clause-
namide [(–)-1, Figure 1] was later found to be a useful
nootropics.2 It exhibited remarkable long-term potentia-
tion (LTP) enhancing capability in hippocampus of rats,3
and is now under clinical trial in China for its potential in
treatment of Alzheimer’s disease. (+)-epi-Clausenamide
[(+)-2, Figure 1] is a non-natural diastereomer of (–)-1
that showed twice the magnitude of LTP enhancement as
that of (–)-1, and thereby a more promising nootropics.3
Moreover, (–)-3 (Figure 1), the 3-deoxy analogue of (–)-
2, was identified as an inhibitor of 17-β-hydroxy-steroid
dehydrogenase II (17-β-HSD II) and therefore could be
useful in preventing the onset of osteoporosis.4 Based
upon these biological findings, enantioselective synthesis
of (+)-2 and (–)-3 merits an interesting subject of study.
O
6
N
N
N
Me
Me
Me
HO
HO
HO
(–)-1 (3S,4R,5R,6S)
(+)-2 (3R,4S,5S,6S)
(–)-3 (4R,5R,6R)
H
OH
O
H
N
Me
O
O
N
Me
O
4
5
Figure 1 Structure of clausenamide, bioactive unnatural analogues,
and synthetic precursors
As illustrated in Scheme 1, our synthetic plan for 2 and 3
started with the known condensation of serine derivative
6 with Meldrum’s acid, which gives β-keto lactam 7. For
both antipodes of 6 are readily available, it is easy to de-
fine the C5 configuration in the molecule of 7. After trans-
fer of 7 into a suitable sulfonate (8), the C4-phenyl was to
be introduced by Suzuki–Miyaura coupling to give 9 in
enantiomerially pure form. Catalytic hydrogenation of 9
was then expected to give rise to the C4–C5 cis geometry
(10). The threo-selective Grignard reaction of 10 first ob-
served by Hartwig and Born,5 nevertheless, would be uti-
lized to introduce the C6-phenyl to afford 3, and finally
the C3–OH was to be installed by oxidation of the metal
enolate to accomplish the enantioselective synthesis of 2.
Hartwig and Born first reported the total synthesis of (±)-
1.5 Thereafter, Huang et al. contributed a more advanced
five-step biomimetic synthesis, in which the cyclization of
4 was the key step to deliver the precursor named as
clausenamidone (5, Figure 1).6 Huang’s strategy was later
utilized in several asymmetric syntheses of (+)- and (–)-1
in combination with varied asymmetric accesses to the
2,3-epoxy-cinnamyl moiety in the molecule of 4 (or its
equivalence).7 However, the same strategy is not applica-
Based upon this plan, L-serine derivative L-6 was selected
the starting material of (–)-3 (Scheme 2). The procedure
previously reported by Ma9 was followed to carry out the
condensation of (+)-6 with Meldrum’s acid and the fol-
lowing ring closure. Because the resulting β-keto lactam
suffered significant decomposition during chromato-
SYNLETT 2012, 23, 1217–1220
Advanced online publication: 26.04.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290804; Art ID: ST-2012-W0034-L
© Georg Thieme Verlag Stuttgart · New York

1218
L. Zhang et al.
LETTER
RO2SO
H
Table 1 Optimization of the Suzuki Couplinga
O
COOH
H
TBSO
O
OH
O
N
5
TsO
NHBoc
N
PdCl2
ligand
Boc
TBSO
Boc
B
TBSO
H
OH
6
7
8
H
+
O
solvent
base
N
O
N
Boc
R
Boc
R
H
(+)-8 R = TBSO
(+)-8a R = H
(+)-8b R = Ph
(+)-9 R = TBSO
(+)-9a R = H
(+)-9b R = Ph
4
4
5
H
H
O
O
N
N
Boc
Me
TBSO
O
Baseb
Solventc
9
10
Entry Tosylate Ligand
Yield
(%)d
H
N
H
OH
1
2
8
DPPF
DPPF
DPPF
DPPE
DPPB
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
Cs2CO3 THF–H2O (5:1)
Cs2CO3 THF–H2O (5:1)
Cs2CO3 THF–H2O (5:1)
Cs2CO3 THF–H2O (5:1)
Cs2CO3 THF–H2O (5:1)
Cs2CO3 THF–H2O (5:1)
0
86
81
0
3
H
H
O
8a
8b
8
6
O
N
Me
Me
HO
HO
3
3
2
4
Scheme 1 Synthetic plan for 2 and 3
5
8
0
graphic purification, it was subjected to the next step of
elaboration without isolation, and stable (+)-8 was ob-
tained in 74% yield over two steps.
6
8
8
7
8
KF
THF–H2O (5:1)
THF–H2O (5:1)
THF–H2O (5:1)
THF–H2O (5:1)
10
39
48
62
8
8
K2CO3
NaOH
CsF
TsO
O
COOH
NHBoc
H
H
b
a
9
8
R
O
O
N
N
Boc
10
11
8
R
Boc
R
L-6 R = TBSO
L-6a R = H
(+)-8 R = TBSO
(+)-8a R = H
(+)-8b R = Ph
8
CsF
benzene–H2O (5:1) 73
L-6b R = Ph
a Reaction conditions: phenylboronic acid (1.5 equiv), PdCl2 (15
mol%), ligand (15 mol%), base (3.0 equiv), 65 °C.
b Other bases proved ineffective: KBr, NaOH, KOH, K3PO4.
c The PdCl2/DPPP/CsF-promoted reaction failed to give coupling
product in DMF.
Scheme 2 Reagents and conditions: (a) Meldrum’s acid (1.0 equiv),
EDCI (1.2 equiv), DMAP (1.48 equiv), r.t., 5% KHSO4 workup, and
then heated to reflux in EtOAc; (b) TsCl (1.2 equiv), Et3N (1.3 equiv),
0 °C.
d Isolated yield.
Simple tosylate substrates that differ from (+)-8 only by
lacking the C5 substituents were known to be able to un-
dergo successful Suzuki coupling with phenylboronic
acid in the presence of PdCl2/DPPF.10 However, our ini-
tial attempts on the reaction of (+)-8 proved to be failure
since no desired product was detected (Table 1, entry 1).
In order to evaluate the quality of our sample of
PdCl2/DPPF, we synthesized substrates 8a and 8b
(Scheme 2), both bearing all-carbon substituent at C5, and
found both of them afforded coupling products 9a and 9b
in good yield (Table 1, entries 2 and 3), implying that the
presence of an oxygen-containing substituent at C5 exert-
ed strong impact on the behavior of (+)-8 during the pro-
cess of PdCl2/DPPF catalysis. Therefore, other commonly
employed bidentate phosphine ligands, including DPPE,
DPPB, and DPPP, were examined (Table 1, entries 4–6,),
and fortunately, the last one was found to be helpful, even
though the yield of (+)-9 was extremely low. Upon further
screening of a variety of additive bases other than Cs2CO3
(Table 1, entries 7–10),11 we found that CsF helped to de-
liver the desired (+)-9 in an optimal yield of 60% without
affecting the TBS group. Furthermore, additional experi-
ments revealed that a better yield could be achieved by us-
ing a benzene–H2O mixture as solvent (Table 1, entry
11).12
With the key Suzuki–Miyaura coupling reaction opti-
mized, we went on embarking the synthesis of (–)-3
(Scheme 3). Compound (+)-9 was hydrogenated at medi-
um pressure (3.45 bar) in the presence of 10% Pd/C to
give 4,5-cis-substituted (–)-11 in 85% yield,13 which was
subsequently treated with TFA to remove the N-Boc
group and N-methylated with MeI and NaH to give (–)-12
in 80% overall yield.14 After preparation of (–)-13 in 98%
yield from (–)-12 by cleavage of the TBS ether with
TBAF, the chemistry Hartwig and Born described5 in ra-
cemic form was executed. Hence, (–)-13 was subjected to
the Swern oxidation delivering (–)-14 and then Grignard
reaction with phenyl magnesium bromide. As it was ex-
pected, the reported threo-selective addition was highly
reproducible, and (–)-315 was isolated in 53% yield over
two steps.
After successful enantioselective synthesis of (–)-3, we
moved on to the preparation of (+)-2 by following the
same sequence. As it is shown in Scheme 4, the 11-step
transformation starting from D-6 to (+)-3 proved straight-
Synlett 2012, 23, 1217–1220
© Georg Thieme Verlag Stuttgart · New York

LETTER
Enantioselective Synthesis of (+)-epi-Clausenamide
1219
forward, giving the precursor of target molecule in 18.2%
overall yield. Interestingly, the final step to (+)-2 appeared
to be different from literature report, because a similar
Davis oxidation of lithium enolate was reported ineffec-
tive,5 but in our case the desired product (+)-216 was iso-
lated in 85% yield when the same oxidant was applied
after treatment of (+)-3 with excessive LDA.
H
H
a
b
H
H
H
80%
(2 steps)
85%
O
O
O
N
N
N
Boc
(+)-9
Boc
Me
TBSO
TBSO
H
TBSO
(–)-11
(–)-12
In conclusion, we report for the first time the successful
enantioselective synthesis of (+)-217 and (–)-3, two bio-
logically important close analogues of clausenamide,
from D- and L-serine derivatives, respectively. With the
main content assigned to the optimization of a previously
unknown Suzuki–Miyaura coupling reaction, this study
provided a convenient approach to the target molecules
and thereby will help facilitate the related biological stud-
ies.
H
c
98%
d
e
H
H
70%
75%
O
O
N
N
Me
(–)-13
Me
HO
O
(–)-10
H
H
O
N
Me
(–)-3
HO
Acknowledgment
We are in debt to the Ministry of Science and Technology of China
for their generous financial support (2009ZX09501-006).
Scheme 3 Reagents and conditions: (a) H2 (3.45 bar), 10% Pd/C; (b)
1. TFA (1.2 equiv), CH2Cl2, 30 min, NaHCO3 workup; 2. MeI (1.3
equiv), NaH (1.3 equiv), DMF; (c) TBAF (1.1 equiv), THF; (d) oxalyl
chloride (1.5 equiv), DMSO (2.0 equiv), Et3N (3.0 equiv), –78 °C; (e)
PhMgBr (1.0 equiv), THF, 0 °C.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.onmornifIatngonimSorfniturItagponiSutpor
TsO
References and Notes
H
COOH
NHBoc
D-6
b
a
TBSO
(1) Yang, M. H.; Cao, Y. H.; Li, W. X.; Yang, Y. Q.; Chen, Y.
Y.; Huang, L. Acta Pharm. Sin. 1987, 22, 33.
O
75%
74%
(2 steps)
N
Boc
(–)-8
TBSO
H
(2) (a) Liu, Y.; Shi, C. Z.; Zhag, J. T. Acta Pharm. Sin. 1991, 26,
166. (b) Duan, W. Z.; Zhang, J. T. Acta Pharm. Sin. 1997,
32, 259. (c) Duan, W. Z.; Zhang, J. T. Chin. Med. J. 1998,
111, 1035. (d) Tang, K.; Zhang, J. T. Life Sci. 2004, 74,
1427. (e) Hu, J. F.; Chu, S. F.; Ning, N.; Yuan, Y. H.; Xue,
W.; Chen, N. H.; Zhang, J. T. Neurosci. Lett. 2010, 483, 78.
(3) Feng, Z. Q.; Li, X. Z.; Zheng, G. J.; Huang, L. Bioorg. Med.
Chem. Lett. 2009, 19, 2112.
H
c
d
82%
H
H
H
85%
O
O
O
N
N
N
Boc
(–)-9
Boc
Me
TBSO
TBSO
TBSO
(+)-11
(+)-12
(4) (a) Cook, J. H.; Barzya, J.; Brennan, C.; Lowe, D.; Wang,
Y.; Redman, A.; Scott, W. J.; Wood, J. E. Tetrahedron Lett.
2005, 46, 1525. (b) Gunn, D.; Akuche, C.; Baryza, J.; Blue,
M. L.; Brennan, C.; Campbell, A. M.; Choi, S.; Cook, J.;
Conrad, P.; Dixon, B.; Dumas, J.; Ehrlich, P.; Gane, T.; Joe,
T.; Johnson, J.; Jordan, J.; Kramss, R.; Liu, P.; Levy, J.;
Lowe, D.; McAlexander, I.; Natero, R.; Redman, A. M.;
Scott, W.; Seng, T.; Sibley, R.; Wang, M.; Wang, Y.; Wood,
J.; Zhang, Z. Bioorg. 2005, 15, 3053.
H
H
g
f
e
H
H
70%
78%
98%
O
O
N
N
Me
Me
HO
O
(+)-13
(+)-10
(5) Hartwig, W.; Born, L. J. Org. Chem. 1987, 52, 4352.
(6) (a) Rao, E. C.; Hong, H.; Cheng, J. C.; Yang, G. Z.; Lin, H.
S.; Huag, L. Chin. Chem. Lett. 1994, 5, 267. (b) Rao, E. C.;
Cheng, J. C.; Yang, G. Z.; Yang, M. H.; Huag, L. Acta
Pharm. Sin. 1994, 29, 502.
H
H
OH
h
H
H
85%
O
O
N
N
Me
Me
HO
HO
(+)-3
(+)-2
(7) (a) Wang, J. Q.; Tian, W. S. J. Chem. Soc., Perkin Trans. 1
1995, 209. (b) Zhong, C.; Gautam, L. N. S.; Petersen, J. L.;
Akhmedov, N. G.; Shi, X. D. Chem.–Eur. J. 2010, 16, 8605.
(c) Cappi, M. W.; Chen, W. P.; Flood, R. W.; Liao, Y. W.;
Roberts, S. M.; Skidmore, J. S.; Smith, J. A.; Williamson,
N. M. Chem. Commun. 1998, 1159.
(8) Xue, J. J.; Zhou, Y. M.; Yu, X. M. Chin. Chem. Lett. 2011,
22, 1261.
(9) Ma, D. W.; Ma, J. Y.; Ding, W. L.; Dai, L. X. Tetrahedron:
Asymmetry 1996, 7, 2365.
Scheme 4 Reagents and conditions: (a) 1. Meldrum’s acid (1.0
equiv), EDCI (1.2 equiv), DMAP (1.48 equiv); 2. TsCl (1.2 equiv),
Et3N (1.3 equiv), 0 °C; (b) phenylboronic acid (1.5 equiv), PdCl2 (15
mol%), DPPP (15 mol%), CsF (3.0 equiv), benzene–H2O, reflux; (c)
H2, 10% Pd/C, 3.45 bar; (d) 1. TFA (1.2 equiv), CH2Cl2, 30 min,
NaHCO3 workup; 2. MeI (1.3 equiv), NaH (1.3 equiv), DMF; (e)
TBAF (1.1 equiv), THF; (f) oxalyl chloride (1.5 equiv), DMSO (2.0
equiv), Et3N (3.0 equiv), –78 °C; (g) PhMgBr (1.0 equiv), THF, 0 °C;
(h) LDA (3.0 equiv), 2-(methylsulfonyl)-3-phenyl-1,2-oxaziridine
(4.0 equiv), THF, –78 °C.
(10) (a) Yoon-Miller, S. J. P.; Opalka, S. M.; Pelkey, E. T.
Tetrahedron Lett. 2007, 48, 827. (b) Yoon-Miller, S. J. P.;
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1217–1220

1220
L. Zhang et al.
LETTER
dried over Na2SO4. Evaporation of the solvent in vacuo
Dorward, K. M.; White, K. P.; Pelkey, E. T. J. Heterocycl.
Chem. 2009, 46, 447.
afforded a white solid (860 mg). The solid was dissolved in
DMF (10.5 mL) and cooled to 0 °C. NaH (147 mg, 1.3
mmol) was carefully added to the solution under argon. The
mixture was stirred until the evolution of gas had ceased.
MeI (0.31 mL, 1.3 equiv) was added through a syringe, and
the reaction was stirred at r.t. until TLC showed complete
conversion. A sat. aq NH4Cl solution (ca. 5.0 mL) was added
dropwise until pH 6. After the most amount of DMF was
removed by evaporation under reduced pressure, the
(11) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew.
Chem. Int. Ed. 2001, 40, 4544.
(12) Typical Procedure for Suzuki–Miyaura Coupling:
Compound (+)-8 (100 mg, 0.2 mmol, 1.0 equiv),
phenylboronic acid (37 mg, 0.3 mmol, 1.5 equiv), PdCl2 (3.6
mg, 0.02 mmol, 0.1 equiv), and DPPP (8.3 mg, 0.02 mmol,
0.1 equiv) were placed in a three-necked flask with a
magnetic stirring bar and a condenser. The reactor was
evacuated with an oil pump and then flushed with argon.
After this process was repeated for three times, benzene (2.0
mL) was added through a syringe. Upon a clear solution was
formed under stirring, CsF (91 mg, 3.0 equiv in H2O, 0.4
mL) was added through a syringe. The reaction mixture was
stirred at r.t. for 1 h and then heated to reflux (about 12 h).
After cooling to r.t., the reaction mixture was washed with a
sat. aq solution of NaHCO3 (2.0 mL), brine (2.0 mL), and
dried over Na2SO4. Removal of the solvent in vacuo and
chromatography (PE–EtOAc, 10:1) gave (+)-9 (59 mg) as a
white solid. 1H NMR (400 MHz, CDCl3): δ = 7.455 (5 H, s,
ArH), 6.297 (1 H, s, C3-H), 5.090 (1 H, s, C5-H), 4.231 (1
H, dd, J = 2.4, 10.4 Hz, C6-H), 3.808 (1 H, d, J = 10.4 Hz,
C6-H), 1.590 (9 H, s, BocH), 0.731 (9 H, s, t-BuSi), –0.158
(3 H, s, CH3Si), –0.228 (3 H, s, CH3Si). 13C NMR (125 MHz,
CDCl3): δ = 169.063, 159.630, 149.756, 131.365, 130.571,
128.968, 127.122, 121.505, 82.754, 63.401, 60.440, 28.206,
25.581, 17.996, –5.875. ESI-HRMS: m/z calcd for
[C22H33NO4Si + Na]+: 426.2071; found: 426.2060.
[α]D20 +55.0 (c 0.64, CHCl3).
reaction mixture was diluted with EtOAc (10.0 mL) and
washed with H2O (10 mL). The aqueous phase was then
extracted with EtOAc (5 × 10 mL). The organic layers were
combined and washed with brine (50.0 mL) and dried over
Na2SO4. Removal of the solvent in vacuo and chromato-
graphy (PE–EtOAc, 4:1) gave (–)-12 (635 mg, 80% in 2
steps). 1H NMR (400 MHz, CDCl3): δ = 7.358–7.274 (5 H,
m, PhH), 3.760 (1 H, m, C4-H), 3.692 (1 H, m, C5-H), 3.562
(1 H, d, J = 11.2 Hz, C6-H), 3.251 (1 H, d, J = 10.8 Hz, C6-
H), 2.977 (1 H, m, C3-H), 2.920 (3 H, s, NMe), 2.535 (1 H,
dd, J = 8.4, 15.6 Hz, C3-H), 0.842 (9 H, s, t-BuSi), –0.091 (3
H, s, CH3Si), –0.121 (3 H, s, CH3Si). 13C NMR (75 MHz,
CDCl3): δ = 174.718, 137.498, 128.493, 128.051, 127.803,
127.624, 126.755, 64.983, 59.452, 41.419, 35.213, 28.091,
25.404, 17.630, –6.151, –6.292. ESI-HRMS: m/z calcd for
20
[C18H29NO2Si + H]+: 320.2040; found: 320.2038. [α]D
–21.3 (c 1.11, CHCl3).
(15) Data for (–)-3:
1H NMR (400 MHz, DMSO-d6): δ = 2.29 (3 H, s, NCH3),
2.278 (1 H, d, J = 8.4 Hz, C3-H), 3.057 (1 H, t, J = 13.6 Hz,
C3-H), 3.814 (1 H, dd, J = 8.4, 19.2 Hz, C4-H), 4.161 (1 H,
s, C6-H), 5.348 (1 H, d, J = 4.0 Hz, OH), 7.458–7.185 (10 H,
m, PhH). 13C NMR (75 MHz, CDCl3): δ = 175.351, 141.957,
137.607, 128.297, 127.930, 127.686, 126.862, 126.832,
124.725, 71.307, 70.025, 43.026, 34.586, 30.602. ESI-
HRMS: m/z calcd for [C18H19NO2 + H]+: 282.14920; found:
282.14966. [α]D20 –139.2 (c 0.50, MeOH).
(13) (2R,3R)-tert-Butyl-2-[(tert-butyldimethylsilyloxy)-
methyl]-5-oxo-3-phenylpyrrolidine-1-carboxylate
[(-)-11]:
To a solution of (+)-9 (400 mg, 1.0 mmol) in MeOH (20
mL), 10% Pd/C (40 mg) was slowly added. The mixture was
hydrogenated (3.45 bar) for 12 h. After removal of the solid
material, the filtrate was evaporated to dryness.
Chromatograph of the residue (PE–EtOAc, 20:1) gave
(–)-11 (345 mg, 85%) as a colorless oil. 1H NMR (300 MHz,
CDCl3): δ = 7.388 (5 H, m, ArH), 4.311 (1 H, d, J = 7.8 Hz,
C6-H), 3.942 (1 H, d, J = 10.8 Hz, C6-H), 3.786 (1 H, m, C5-
H), 3.289 (2 H, m, C3-H, C4-H), 2.642 (1 H, dd, J = 8.7, 16.5
Hz, C3-H), 1.613 (9 H, s, BocH), 0.911 (9 H, s, t-BuSi),
–0.001 (3 H, s, CH3Si), –0.021 (3 H, s, CH3Si). 13C NMR
(100 MHz, CDCl3): δ = 173.975, 149.991, 136.679, 128.440,
128.127, 127.350, 82.768, 62.704, 60.348, 41.252, 37.340,
28.068, 25.731, 18.034, –5.884, –5.923. ESI-HRMS: m/z
calcd for [C22H35NO4Si + Na]+: 428.2228; found: 426. 2207.
[α]D20 –3.0 (c 0.99, CHCl3).
(16) Data for (+)-2:
1H NMR (400 MHz, CDCl3): δ = 7.623–7.375 (10 H, m,
PhH), 5.366 (1 H, d, J = 10.4 Hz, C6-H), 4.639 (1 H, s, C5-
H), 4.116 (1 H, d, J = 8.0 Hz, C3-H), 3.845 (1 H, t, J = 9.2
Hz, C4-H), 2.489 (3 H, s, NMe). 13C NMR (100 MHz,
CDCl3): δ = 141.913, 136.126, 128.936, 128.497, 128.127,
127.476, 125.047, 109.630, 70.550, 70.382, 68.319, 52.414,
31.534. ESI-HRMS: m/z calcd for [C18H19NO3 + H]+:
298.14432; found: 298.14426. [α]D20 +205.3 (c 0.48,
MeOH); lit.3 [α]D20 +201 (c 0.25, MeOH).
(17) Both (+)- and (–)-3 gave a single diastereomer when
converted into their respective ester form with (S)-O-
acetylmandelic acid, as indicated by 1HNMR (see
(14) (4R,5R)-5-[(tert-Butyldimethylsilyloxy)methyl]-1-
methyl-4-phenylpyrrolidin-2-one [(–)-12]:
Supporting Information). Both esters were then hydrolyzed,
and the recovered samples of (+)- and (–)-3 showed literally
identical optical rotation on comparison to that of the
original samples {(+)-3: [α]D20 +137.0 (c 0.23, MeOH) vs.
[α]D20 +138.9 (c 0.62, MeOH); (–)-3: [α]D20 –138.0 (c 0.45,
MeOH) vs. [α]D20 –139.2 (c 0.50, MeOH)}. Therefore, the
possibility of epimerization during the process of synthesis,
particularly the steps to (–)- and (+)-8, was precluded.
To a stirred solution of (–)-11 (1.0 g, 2.5 mmol) in CH2Cl2
(17.0 mL) was added TFA (0.48 mL, 2.0 equiv in CH2Cl2
(4.8 mL)] through a syringe at 0 °C. The reaction mixture
was stirred at 0 °C for 0.5 h and then diluted with EtOAc
(20.0 mL). A sat. aq solution of NaHCO3 (ca. 1.0 mL) was
added dropwise to adjust the pH to 7. The organic phase was
then washed with H2O (40.0 mL) and brine (40.0 mL) and
Synlett 2012, 23, 1217–1220
© Georg Thieme Verlag Stuttgart · New York

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